₂-adrenergic receptors (₂AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation, and are the targets for -agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindividual variability, which is not adequately explained by genetic variability in the 5'-flanking or coding region of the intronless ₂AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Arg16) is found within three haplotypes that differ by the number of C's (11, 12 or 13) within a 3'UTR poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the ₂AR (Arg16) coding sequence followed by its 3'UTR with the various polymorphic poly-C tracts. ₂Arg16-11C had 25% lower mRNA expression and 33% lower ₂AR protein expression compared to the other two haplotypes. Consistent with this lower steady-state expression, ₂Arg16-11C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared to ₂Arg16-12C and 13C. However, ₂Arg16-12C underwent 50% less downregulation of receptor expression during -agonist exposure compared to the other two haplotypes. Thus, these haplotypes direct a potential low-response phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (₂Arg16-11C), and, a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation (₂Arg16-12C). This heterogeneity may contribute to the variability of clinical responses to -agonist, and genotyping to identify these 3'UTR polymorphisms may improve predictive power within the context of ₂AR haplotypes in pharmacogenetic studies.